The bis-indolylmaleimide subunit is present in a number of biologically active metabolites isolated from Streptomycetes including Staurosporine, (Tamaoki et al., Biochem. Biophys. Res. Commun. 135: 397-402 (1986); Gross et al., Biochem. Pharmacol. 40: 343-350 (1990)) and Rebeccamycin, (Steglich et al., Angw Chem. Int. Ed. Engl. 19:459 (1980)). The simplest members of this class of compounds are the arcyriarubins, a family of pigments produced by slime molds (Myxomycetes). Id. Bis-indolylmaleimides are selective inhibitors of PKC and show promise as a novel potential therapy for auto immune diseases (Bit, R. A. et al., J. Med. Chem. 361:21 (1993)). The bisindolylmaleimide GF109303X has been recognized as a PKC kinase selective agent, (Bit, R. A. et al., Tetrahedron Letters 34:5623 (1993)) as has the conformational restricted analog, Ro 32-0432 (Wilkinson, S. E., J. Med. Chem. 36:21 (1993)) and also N,N'bridged bisindolylmaleimide macrocycles (Jirousek et al., J. Med. Chem. 39 (14):2664-2671 (1996)).
Several methods are available in the literature to prepare the bis-indolylmaleimide framework including reaction of dihalomaleimides with indole Grignard reagents (Faul et al., Synthesis 12:1511 (1995) and Steglich, W. Tetradron 44: 2887 (1988)), oxidative coupling of indole-3-acetic acid trianions (Bergman et al., Tetrahedron Letters 28:1444 (1987)), and reaction of indolyl-3-glyoxyl chlorides with either indole-3-acetic acid in a Perkin condensation approach or with indole-3-acetimidates (Specter et al., J. Am. Chem. Soc. 76:6208 (1954); Davis, P. D., et al., Tetrahedron Letters 31:5201 (1990), Bit, R. A., Tetrahedron Letters 34:5623 (1993)) to prepare a bisindolylmaleic anhydride which is then converted to a bisindolylmaleimide in a two-step synthesis. Although all of these procedures can be utilized to prepare bisindolylmaleimides, one must use different procedures or multiple steps to prepare unsymmetrical vs. symmetrically substituted bisindolylmaleimides. Thus, there remains a need for a general and efficient method of preparing bis-indolylmaleimides.
The present invention provides a general and very efficient method for the synthesis of these substrates. The syntheses provides a flexibile and powerful methodology for the synthesis of bisindolylmaleimides.